Enantioselectivity of the enterohepatic recycling of carprofen in the dog.
The disposition of the two enantiomers of carprofen (CPF), the (R)-CPF and the (S)-CPF, was investigated after iv administration of the racemate (4 mg/kg) in dogs equipped with a chronic bile duct catheter. Studies in dogs with diverted bile flow showed that both enantiomers were extensively excreted in bile with 74% of the (R)-enantiomer and 92% of the (S)-enantiomer from the iv administered dose being recovered in the bile as the respective glucuronide conjugates. The direct administration of acidic bile containing acyl-glucuronides of CPF in the duodenum showed that both conjugated enantiomers led to high CPF enantiomer systemic availability. However, comparison of CPF pharmacokinetics between dogs with nondiverted bile flow and dogs with diverted bile flow suggested that CPF was subjected to enantioselective enterohepatic recycling (EHC) and that only the (S)-CPF was recycled. The absence of EHC for the (R)-CPF is hypothesized to be the result of formation of glucuronidase-resistant isoglucuronides (epimers) to a greater extent for the (R)-CPF than for the (S)-CPF.
Priymenko
N
N
Ecole Nationale Vétérinaire de Toulouse, Unite Associée INRA de Physiopathologie et Toxicologie Exp-erimentales, Toulouse, France.
Garnier
F
F
Ferre
J P
JP
Delatour
P
P
Toutain
P L
PL
D000818:Animals; D001646:Bile / Q000737:chemistry; D002227:Carbazoles / Q000097:blood / Q000493:pharmacokinetics*; D004285:Dogs; D005965:Glucuronates / Q000032:analysis / Q000493:pharmacokinetics; D005966:Glucuronidase / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000502:physiology*; D008099:Liver / Q000502:physiology*; D008297:Male; D010599:Pharmacokinetics; D013237:Stereoisomerism
D002227:Carbazoles; D005965:Glucuronates; D005966:Glucuronidase; C007005:carprofen